keratan-sulfate and Wallerian-Degeneration

Wallerian degeneration is a fundamental process of axonal degeneration distal to the injury site. Although axonal degeneration itself is accomplished in a few days, the subsequent process of removing debris, including myelin debris, in the central nervous system takes more time. Since this debris is a potent inhibitor of axonal regeneration, the removal process is critical for functional recovery after neuronal injuries. Although it is known that microglia/macrophages are involved in this process, the underlying mechanisms are not fully understood. Here, we found that keratan sulfate (KS) expression was induced far from the injury site after spinal cord injury. A hemilateral section of the spinal cord at the third cervical level induced KS expression in a restricted area of the ipsilateral column at the first lumbar level 1 week after injury. This localized KS expression lasted for at least 1 month after injury. The KS signal was merged with a portion of Iba1-positive cells, suggesting that a subpopulation of microglia/macrophages expressed KS. KS-positive cells expressed CD68 and CD86, but not CD206 or arginase 1, suggesting that these microglia/macrophages were in an activated state probably polarized to M1. Our study has explored for the first time the relation between KS expression and activation of microglia/macrophages in Wallerian degeneration.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Calcium-Binding Proteins; Female; Interleukin-1beta; Keratan Sulfate; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Spinal Cord Injuries; Wallerian Degeneration

The monoclonal antibody (MAb) 5D4 against a keratan sulfate (KS) epitope of bovine cartilage proteoglycan stains ramified microglia in the rat brain. In this study we show that 5D4-positive microglia is abundant in the normal rat spinal cord and nearly absent during both the active and recovery phase of experimental autoimmune encephalomyelitis (EAE) in myelin-immunized Lewis rats. In contrast, during Wallerian degeneration of the optic nerve the density of KS-immunoreactive microglia remains constant. KS immunoreactivity is absent from both normal and transected sciatic nerves, and spinal nerve roots. On immunoblots of spinal cord extracts MAb 5D4 stains a novel type of KS proteoglycans (KSPGs) with an apparent molecular weight mainly between 140 and 200 kd, which significantly decrease in acute EAE. Our data suggest that high levels of KSPG expression correlate to a downregulated immunophenotype of resident macrophages in the nervous system. The lack of detectable KS in peripheral nerve points to a divergent differentiation of bone marrow-derived resident macrophages in the peripheral and central nervous systems and may partially account for the rapid macrophage response to axonal injury in the peripheral nervous system. Downregulation of microglial KSPG could be a prerequisite for a rapid inflammatory response in the central nervous system.

Topics: Animals; Autoimmune Diseases; Central Nervous System; Down-Regulation; Encephalomyelitis; Female; Keratan Sulfate; Microglia; Peripheral Nervous System; Rats; Rats, Inbred Lew; Wallerian Degeneration